Antifungal Drugs2014

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Teijo I. Saari and Klaus T. Olkkola

27 Antifungal drugs

ALLYLAMINES [SEDA-32, 491;SEDA-33, 541; SEDA-34, 427]

Terbinane [SED-15, 3316; SEDA-32,

491; SEDA-33, 541; SEDA-34, 427]

Observational studies Serious adverseevents due to systemic terbinane reportedto the National Danish Adverse ReactionDatabase over 10-year period have beenanalysed [1R]. During this time 263 patients(140 women and 123 men) developed anadverse event that was attributed to ter-binane. Of these 26% (n ¼ 78) were consid-ered serious. The most common serious

adverse events were: skin and subcutane-ous tissue disorders (n ¼ 60, 30%), nervoussystem disorders (n ¼ 26, 13%), andhepatobiliary disorders (n ¼ 29, 15%).The rate of serious adverse events cor-rected for consumption of terbinane(dened daily doses, DDD) during thestudy was 4.2 per 1000 DDD (78 seriousadverse events, 18 534 DDD).

Drug–drug interactions Risperidone A 43-year-old boy with bipolar schizoaffectivedisorder who was taking risperidone wasgiven terbinane for onychomycosis; hehad an exacerbation of his psychotic symp-toms [2A]. Terbinane was withdrawn andhe rapidly stabilized within 12 days. Ter-binane is an inhibitor of CYP2D6, whichis the main metabolic pathway of risperidone.

AMPHOTERICIN [SED-15, 192;SEDA-32, 493; SEDA-33, 542; SEDA-

34 , 42 7]

Amphotericin B Lipid Complex(ABLC)

Nephrotoxicity Amphotericin lipid complexhas been evaluated in the management of invasive fungal infections in immunocompro-mised patients in a retrospective review of observational studies [3R]. Amphotericinlipid complex was associated with 80% and60% response rates in patients with con-

rmed fungal infections and in empiricaltreatment respectively. Compared with con-ventional amphotericin, there is a substan-tially lower incidence of nephrotoxicityassociated with amphotericin lipid complex.Intranasal administration used in prophylaxisof invasive fungal infection may emerge as auseful treatment strategy in the future.

Liposomal amphotericin (L-AmB)

Observational studies Hepatotoxicity andnephrotoxicity have been retrospectivelyevaluated in 100 consecutive patientsreceiving L-AmB [4c]. According to theinclusion criteria, 75 patients were included.Based on increases in laboratory values(bilirubin and aminotransferases), therewas hepatotoxicity in 16 (21%) of the

patients. The analysis revealed no furthercorrelates to explain this adverse effect.Nephrotoxicity developed in 42 (56%) of the patients who received L-AmB, but 31(74%) of these received intravenous con-trast media and 38 (90%) received other

483

Side Effects of Drugs, Annual 35J.K. Aronson (Editor)ISSN: 0378-6080http://dx.doi.org/10.1016/B978-0-444-62635-6.00027-9# 2014 Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/B978-0-444-62635-6.00027-9http://dx.doi.org/10.1016/B978-0-444-62635-6.00027-9


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concurrent nephrotoxins. Age, cumulativedose, dose escalation, and exposure to con-comitant nephrotoxins and intravenouscontrast media were independently associ-

ated with nephrotoxicity. Logistic regres-sion analysis showed that age was the onlysignicant variable that determinednephrotoxicity.

Cardiovascular A hypersensitivity reactionwith ST segment elevated myocardial infarc-tion (Kounis syndrome) has been attributedto liposomal amphotericin B [5A].

• A 71-year-old man with severe coronary

artery disease and previous coronary arterybypass grafting received intravenous L-AmBfor oral histoplasmosis; 1 hour after the startof the infusion he developed a hypersensitivityreaction with subsequent ST elevation.

Nervous system A healthy 38-year-old manreceived liposomal amphotericin B for cuta-neous leishmaniasis and shortly after devel-oped memory dif culties and confusion [6A].The symptoms resolved over a few weeks.

Urinary tract A 36-year-old Chinese manwith remitting fever, anemia, and pancyto-penia received liposomal amphotericin10 mg/day for visceral leishmaniasis; the dosewas increased to 150 mg/day during 1 weekand his symptoms resolved, but he developedacute renal damage, and L-AmB was with-drawn [7A]. Two maintenance doses of 100 mg/day L-AmB were administered sub-sequently without further symptoms.

ANTIFUNGAL AZOLES[SED-15, 301; SEDA-32, 497; SEDA-

33 , 54 5; SED A- 34, 42 8]

Drug–drug interactions withantifungal azoles

Alitretinoin The effects of ketoconazole onthe pharmacokinetics of alitretinoin havebeen studied in 54 healthy men [ 8C ]. Ali-tretinoin AUC was reduced by 21% andC max by 35% after ketoconazole.

Amiodarone A 65-year old Caucasian manwith extensive ischemic stroke was givenintravenous amiodarone for atrial brilla-tion; he developed severe hypotension after

receiving the rst dose of itraconazole for candidemia [ 9 A ]. Two months later hereceived intravenous itraconazole againand developed hypotension and cardiacarrest. Resuscitation was successful and itra-conazole was changed to caspofungin.

Atazanavir A 56-year old man with HIV and Candida infection was treated successfully using atazanavir during voriconazoletherapy [ 10 A ]; atazanavir does not affect voriconazole metabolism by affectingCYP2C19, but CYP3A inhibition causedby voriconazole should be considered whenadjusting atazanavir doses.

Coumarin anticoagulants A 67-year-oldman who was taking itraconazole was givenwarfarin for a deep vein thrombosis; the plasma concentrations of warfarin startedto increase and the INR was 2.43 on day

10 [ 11 A

]. After withdrawal of warfarin, the plasma concentrations started to fall.

Esomeprazole A 26-year-old woman withacute lymphoblastic leukemia and a history of drug abuse received intravenous voriconazole,oral methadone, and oral esomeprazole; 4 daysafter starting voriconazole she developedventricular bigeminy without prolongationof the QT interval [ 12 A ]. Voriconazole andmethadone concentrations were subsequently

high. After withdrawal of esomeprazole andreduction of the dose of methadone, theelectrocardiogram normalized.

Fesoterodine Fesoterodine is an oral anti-muscarinic drug. In a two-way, open, cross-over, randomized study in 28 healthy subjects there was no clinically signi cant interaction with uconazole [ 13c ].

Neratinib Neratinib is a low molecular weight, orally administered, irreversiblehuman epidermal growth factor receptor 1, 2, and 3 tyrosine kinase inhibitor. Co-administration of neratinib with ketocona-zole, an inhibitor of CYP3A, to 24 healthy

484 Chapter 27 Teijo I. Saari and Klaus T. Olkkola


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subjects increased neratinib C max by 3.2times and AUC by 4.8 times compared withneratinib alone [ 14C ]. These results suggest that neratinib is a substrate of CYP3A and

is susceptible to interactions with CYP3Ainhibitors. Thus, dosage adjustments maybe needed if neratinib is administered with such compounds.

Oxycodone In a retrospective medical recordreview of nine patients with cancer who tookoxycodone during voriconazole treatment there was enhanced analgesia and an increasein the frequency of adverse events [ 15 A ].

Panobinostat (LBH589) Panobinostat is ahistone deacetylase inhibitor, which is partlymetabolized by CYP3A in vitro. In a prospec-tive study in 14 patients with metastatic solidtumors, who took panobinostat 20 mg orallyafter exposure for 4 days to oral ketoconazole400 mg/day, the C max and AUC of panobino-

stat. were increased 1.6 and 1.8 times respec-tively; t max and half-life were unchanged [ 16

c ].

Tacrolimus The extent of the interaction of voriconazole and itraconazole with tacro-limus has been described during 12 monthsof follow-up [ 17 C ]; the daily dose of tacro-limus was on average increased by 76% and64% after itraconazole and voriconazolewere withdrawn. However, there were nodifferences in ef cacy or renal toxicity.

Tamsulosin Co-administration of ketocona-zole 400 mg/day for 5 days with tamsulosin

0.4 mg/day to 24 healthy volunteers increasedthe geometric mean values of C max and AUC by 2.2 and 2.8 times [ 18c ]. The pharmaco-kinetic changes were not associated with clini-cally signi cantly altered pharmacodynamics.

Vandetanib In a phase I study of the effectsof itraconazole on the pharmacokinetics of vandetanib were studied [ 19c ]. Vandetanibexposure was increased signi cantly by

about 9% during itraconazole administra-tion, but this increase is unlikely to haveany clinical consequences.

Vincristine An obese 41-year-old Caucasianman (BMI 36 kg/m 2 ) with a T-cell lymphoma

received intravenous voriconazole 4 mg/kgbetween chemotherapy cycles; there was anunexpected increase in AUC due to reducedclearance of voriconazole [ 20 A ]. Despite a

reduction in dose, the clearance decreased further and the AUC increased. The patient was a carrier of the CYP2C19*2/*2 alleleand was a poor metabolizer. Voriconazolewas withdrawn 3 days before the second cycleof chemotherapy, but nevertheless the patient had adverse reactions that could be attributedto an interaction of voriconazole with vincris-tine. Plasma concentration monitoring andCYP2C19 genotyping together with adminis-tration of a non-triazole antifungal beforechemotherapy may be required to prevent serious vincristine neurotoxicity.

Voriconazole Concomitant use of ucona-zole reduced interindividual variability andincreased voriconazole plasma concentra-tions signi cantly in healthy subjects [ 21c ].The effect was most signi cant in CYP2C19extensive metabolizers.

Fluconazole [SED-15, 1377; SEDA-32, 502; SEDA-33, 551; SEDA-34, 430]

Immunology A 29-year-old Hispanic womanwith HIV/AIDS developed a hypersensitiv-ity reaction after the rst oral dose of 400 mg uconazole; uconazole was consid-ered necessary and the patient underwentdesensitization, starting with 200 micro-grams of oral uconazole [22A]. The dosewas increased gradually every 6 hours untila dose of 200 mg was reached. The patienttolerated the therapeutic dose of 200 mgafter 2 days.

Itraconazole [SED-15, 1932; SEDA-32, 504; SEDA-33, 552; SEDA-34, 430]

Nervous system Severe neuropathy and peripheral edema has been attributed toitraconazole [23A].

485 Antifungal drugs Chapter 27


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• A 72-year-old man with severe asthma tookitraconazole for Aspergillus fumigatus infectionand 1 month later developed progressive bilat-eral ankle edema. The dosage was reduced, butthe peripheral edema persisted and he devel-oped weakness in all four limbs. Itraconazolewas withdrawn, and the edema resolved. After6 weeks the patient became bed bound owingto muscle weakness, but he gradually recov-ered during neurorehabilitation.

Ketoconazole [SED-15, 1269; SEDA- 34, 430]

Endocrine The effect of ketoconazole for

3 weeks on the hypothalamic–pituitary–adrenal axis was evaluated in six elderlytreatment-resistant depressed patients;there was no major increase in cerebro-spinal uid corticotropin-releasing hor-mone concentrations [24A].

Musculoskeletal A 64-year-old man tooksimvastatin and fenobrate for dyslipide-mia and developed hematuria and muscleweakness after an increase in the dose of ketoconazole to treat prostate cancer[25A]. He developed rhabdomyolysis andacute renal failure, after which ketocona-zole, fenobrate, and simvastatin werewithdrawn. The symptoms resolved after10 days of hemodialysis.

Pregnancy A 26-year-old pregnant womantook ketoconazole (200 mg bd) to treatCushing’s syndrome, which had been diag-

nosed 9 weeks before the pregnancy [26A

].Ketoconazole was withdrawn and she gavebirth to a healthy boy at 34 weeks.

Posaconazole [SED-15, 2905; SEDA- 32, 504; SEDA-33, 553; SEDA-34, 430]

Drug–drug interactions Posaconazole phar-macokinetics and CYP3A-mediated drug-

interactions have been reviewed [27

R

].Posaconazole is a potent CYP3A inhibitor,but extensive pharmacokinetics studieswith posaconazole and putative substrateswith extensive rst-pass metabolism arelacking. Posaconazole increases plasma

concentrations of vinca alkaloids, tacroli-mus, sirolimus, everolimus, midazolam,HMG-CoA reductase inhibitors (statins),some antidysrhythmic agents (e.g. cisapride

and quinidine), and calcium channel blockers. Phenytoin, rifabutin, and ciclosporin signicantly reduce the Cmax andAUC of posaconazole.

Voriconazole [SED-15, 3688; SEDA-32, 505; SEDA-33, 554; SEDA-34, 431]

Cardiovascular Prolongation of the QT interval is a marker for ventricular dysrhyth-mias, which can be life threatening. Threepatients developed prolongation of the QTinterval and severe dysrhythmias after tak-ing voriconazole [28A,29A]. Variant poly-morphisms of CYP2C19, which is the mainroute of metabolism of voriconazole, cancontribute substantially to the wide variabil-ity in voriconazole pharmacokinetics, andmay contribute to increased serum vorico-

nazole concentrations and prolongation of the QT interval in certain patients.

• A 15-year-old-boy developed a prolongedQTc interval from 380 to 500 ms after takinga loading dose of voriconazole (6 mg/kg intra-venously) for fungal endocarditis. He devel-oped torsade de pointes, which wassuccessfully terminated with debrillation,intravenous magnesium, and lidocaine. Vori-conazole was changed to caspofungin and theQTc interval normalized (430 ms).

•

A 12-year-old girl with pulmonary aspergillo-sis was treated with intravenous voriconazoleand 11 days later developed ventricularbigeminy and trigeminy. The QTc intervalwas prolonged to 570 ms and there was hypo-kalemia (2.8 mmol/l) and hypomagnesemia(0.7 mmol/l). After withdrawal of voriconazoleand treatment with lidocaine, potassium, andmagnesium, the electrolyte concentrationsand QTc interval normalized (QTc 390 ms).There were no further dysrhythmias. He waslater treated successfully with voriconazolewithout prolongation of the QT interval.

•

A 70-year-old Japanese man with acutemyeloblastic leukemia developed severe dys-rhythmias after receiving intravenous voricona-zole for a neutropenic fever. The prolonged QTcinterval normalized after voriconazole was with-drawn. Two days later he became febrile againand was rechallenged with voriconazole.



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Torsade de pointes recurred and voriconazolewas withdrawn; 1 day later he developed a pulse-less polymorphous ventricular tachycardianecessitating cardiopulmonary resuscitation. Aprolonged QT interval was the only nding atthis point.

Sensory systems Frequent visual hallucina-tions and abnormal liver function tests wereattributed to voriconazole treatment forfungal retinitis in a 43-year-old Indianwoman with Wegener’s granulomatosis;the symptoms started 7 days after the startof treatment and resolved after voricona-zole was withdrawn [30A].

Gastrointestinal A 35-year-old man withacute myelogenous leukemia took vorico-nazole for invasive pulmonary aspergillosisand after 5 days developed pseudomembra-nous colitis [31A]. Voriconazole was with-drawn and oral metronidazole started. Thesymptoms resolved completely.

Liver A 46-year-old woman developedaspergillosis after lung transplantation and

asymptomatic progressive cholestatic hepatitisafter taking oral voriconazole 200 mg bd for10 days [32A]. The dosage of voriconazolewas adjusted to 100 mg bd, after which theliver enzymes started to normalize. Trough

voriconazole concentrations were satisfac-tory after dosage adjustment.

Hepatotoxicity was evaluated retrospec-tively in a cohort study in 84 patients taking

off-label high-dose voriconazole and 25 con-trols taking normal doses [33C]. Multivariateanalysis showed that dose and duration of therapy were predictive of hepatotoxicity.However, differences in liver function werenot observed.

Skin Cases of voriconazole-induced photosensitivity continue to be reported. In 30patients, median age 10 years, in whom 196voriconazole plasma trough measurementswere made during 2135 days of voriconazoletherapy, voriconazole plasma concentra-tions varied widely. There was a signicantrelation between plasma concentrationsabove the usual target range and photo-sensitivity [34C]. However, another reportdeals with two boys, aged 4 and 5 years,who underwent intensive chemotherapy formalignancies were given voriconazole anddeveloped severe photosensitivity after sev-

eral months, despite low to normal serumvoriconazole concentrations [35A]. In onecase the rash worsened when retinoic acidwas added. The EIDOS and DoTS descrip-tions of this reaction are shown in Figure 1.

EIDOS

DoTS

Manifestations (clinical)

Erythema, vesicles, and blisters

Pseudoporphyria and

porphyria cutanea tarda

Risk of skin tumors

Extrinsic species (E)

Voriconazole

Intrinsic species (I)

Elements of the skin; DNA

Sequela (the adverse reaction)

Photosensitivity (?phototoxic)

Outcome (the adverse effect)

Free radical-induced damage

Distribution

Skin

Dose-responsiveness

Collateral

Time-course

Early

permanent

Susceptibility factors

Genetic (?CYP2C19 polymorphisms)

Age

Physiology (skin type)Drugs (immunosuppressants; vitamin A;

other photosensitizing drugs)

Diseases (HIV-AIDS)

Modifying factors

Sunlight (especially UVA)

Figure 1 The EIDOS and DoTS descriptions of voriconazole-induced photosensitivity.



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Immunologic A 28-month-old boy withautosomal recessive chronic granulomatousdisease developed facial lupus-like lesionsafter taking voriconazole [36A].

Voriconazole-associatedperiostitis

Voriconazole has been reported to havecaused periostitis [ 37 A ]. Voriconazole formu-lations contain uoride, and the mechanism of this adverse reaction has been linked to accu-mulation of uoride. The EIDOS and DoTSdescriptions are shown in Figure 2.

Voriconazole contains three uorineatoms, and a 400 mg dose contains 65 mg of uoride [ 38c ]. In comparison, municipal tapwater contains uoride in a concentration of about 1 mg/l, resulting in daily uoride exposure of 2 –4 mg [ 39S ]. Plasma uoride con-centrations are typically raised in patientswho have taken voriconazole for at least

6 months, and markedly high concentrationshave been encountered in some cases. Cau- sality is further suggested by fast recoveryafter voriconazole withdrawal. Low vitaminD concentrations are associated with uorosis, and some reports have suggested that

vitamin D with ascorbic acid supplementa-tion could ameliorate uorosis [ 40 A ].

Fluoride integrates as uorapatite into thebone crystal structure and promotes bone

formation by stimulating osteoblasts. Theintegration of uorapatite into bone causesalterations in bone crystal size and structure,making these more resistant to resorption.Ultimately this increases bone density andleads to osteosclerosis, which is associatedwith brittleness, exostoses, pain, reducedmechanical competence of bone, andincreased susceptibility to fractures [ 41c ].

Fluoride intoxication resembles hyper-trophic osteoarthropathy and periostitis defor-mans, and several common features havebeen observed in skeletal imaging. Symmetri-cal diffuse periosteal reactions, includingosteosclerosis and hyperostotic periostitis,have been described, together with osteoporo- sis, ligamentous calci cation, and periarticular changes; these have been located in various parts of the skeleton. In contrast to hyper-trophic osteoarthropathy, voriconazole-induced periostitis is strongly associated with

a raised alkaline phosphatase and characteris-tically shows no digital clubbing.

Cause Several etiological explanations maybe considered for voriconazole-associated uorosis. Fluorine is organically bound in

EIDOS

DoTS

Manifestations (clinical)

Brittleness, exostoses, pain,

reduced mechanical competence,

risk of fractures

Sequela (the adverse reaction)

Periostitis

Outcome (the adverse effect)

Fluorapatite-induced osteoblast

stimulation, osteosclerosis

Extrinsic species (E)

Voriconazole

Intrinsic species (I)

Apatite in the bone

Distribution

Bone

Dose-responsivenessCollateral

Time-courseLate

Susceptibility factorsGenetic (CYP2C19 polymorphisms)

Drugs (fluoride)

Diseases (renal function)

Modifying factors

?Low vitamin D

Manifestations (test results):

Raised alkaline phosphatase;

raised plasma fluorine

concentrations; periosteal

reactions (x-ray)

Figure 2 The EIDOS and DoTS descriptions of voriconazole-induced periostitis.



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voriconazole, and hepatic oxidative metabo-lism may increase unbound uoride concen-trations after extensive voriconazoleadministration [ 38c ]. Pharmacogenomic var-

iations, especially polymorphisms inCYP2C19 may further alleviate this phenom-enon. Secondly, renal insuf ciency or failuremay increase the risk of toxicity during uo-rine exposure, since its renal clearancedepends on glomerular ltration rate [ 42H ]

Reports of periostitis In a case –control study in 20 transplant patients ve of theten who took voriconazole for at least

7 months had clinical manifestations of peri-ostitis and exostoses [ 38c ]. All those whotook voriconazole had signi cantly raised plasma uoride concentrations comparedwith the controls, whose uoride concentra-tions were in the expected range. Two patients with exostoses were followed moreclosely, and their symptoms improved 2 months after withdrawal of voriconazole.

Five elderly lung transplantation patientsdeveloped diffuse periostitis after chronic

voriconazole treatment [ 43 A

]. All had com- plicated hospital courses and four died inhospital. Plasma uoride concentrationswere not measured.

This association has been further sup- ported by other anecdotal observations.

• A 69-year-old multimorbid woman with aspergillosis complicating lung transplantation devel-oped progressive, disabling, axial andappendicular pain after taking oral voricona-zole 200 mg bd for 3 years. The symptoms lasted for 5 months, with severe right hand pain and swelling for 1 month. Laboratory abnormalities(changes in alkaline phosphatase, aspartateaminotransferase, and parathyroid hormone)were also observed. Radiographs showed nodu-lar, proliferative periosteal reactions bilaterallyin the posterolateral ribs and in multiple phalan- ges of the right hand. The pain and laboratoryvalues resolved after voriconazole was with-drawn and calcitriol was started, to address secondary hyperparathyroidism [ 44 A ].

• A 66-year-old man with a heart transplant tookvoriconazole for pulmonary aspergillosis for 9 months; voriconazole-associated periosteal reactions were seen in the proximal long bonesand thoracic ribs [ 45 A ]. His symptomsimproved after withdrawal of voriconazole.

• A 16-year-old boy with acute myelogenous leu-kemia took voriconazole 300 mg bd to treat

disseminated Fusarium-species infection [ 46 A ]. After 6 months he developed hand pain, nger swelling, fatigue, and diffuse musculoskeletal pain; after 7 weeks of worsening pain, a diffuse periosteal reaction was observed in hand radio-

graphs. The plasma uoride concentration was 24 mmol/l (usual range 1 –4 mmol/l; toxic concen-tration > 15 mmol/l). The pain started to resolve1 week after withdrawal of voriconazole, and 3 weeks later the pain was absent and the plasma uoride concentration was 6.7 mmol/l.

• A 42-year-old woman developed severe diffusemusculoskeletal pain after taking voriconazole for 4 months for fungal endophthalmitis[ 47 A ]. She had nodular periostitis and focal lamellar periosteal reaction around the radial and pretibial diaphyses. Voriconazole waswithdrawn and after 5 days all her symptoms

resolved. At the 4-month follow-up, there was some resolution of the radiographic anomalies.

• A 30-year-old woman with a bilateral lung transplant developed severe diffuse skeletal pain after long-term treatment with voriconazole [ 48 A ].The pain was most intense in the hands, andradiography showed multifocal areas of periosti-tis without clubbing. Her symptoms resolved shortly after withdrawal of voriconazole.

Conclusions The mechanisms by whichchronic voriconazole treatment predisposes

to periostitis seem to involve greatly raised uorine concentrations, although other co-inciding factors are most probably also contrib-utory. Plasma uorine concentrations areusually raised after 6 months of voriconazoleadministration, but symptoms improve rapidlyafter voriconazole withdrawal.

ECHINOCANDINS [SED-15,1197; SEDA-32, 507; SEDA-33, 556;

SEDA-34, 434]

Anidulafungin [SEDA-32, 507]

Observational studies Exposure andadverse reactions to anidulafungin havebeen evaluated in a prospective study in

15 subjects (8 neonates and 7 infants) [49

c

]who received intravenous anidulafungin1.5 mg/kg/day for 35 days. Exposures weresimilar in neonates and infants and compa-rable to exposures in children receivingsimilar weight-based dosages and adults



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receiving 100 mg/day. There were no seri-ous drug-related adverse events. Mild ormoderate adverse events were recorded in53% of the subjects; the most common

adverse event was worsening of hyperbili-rubinemia, leading to withdrawal of anidu-lafungin in one subject.

Management of adverse drug reactions A 50-year-old multimorbid woman with a kidneytransplant and invasive candidosis was trea-ted with anidulafungin after the discovery of abnormal liver function tests resulting frommultiple causes of liver toxicity; previous u-conazole treatment had been withdrawnbecause of possible liver toxicity [50A].

Caspofungin [SEDA-32, 508; SEDA-33, 556; SEDA-34, 434]

Observational studies Caspofungin hasbeen evaluated in a phase II study in 46patients with invasive aspergillosis [51c].

There was no clear relation between caspo-fungin dose and the incidence of adverseeffects, and there were only two events witha probable relationship to caspofungin.

In a review of data from 32 studies in1951 subjects (171 children, 394 healthyadults, and 1386 adult patients), serious-ness, causality, and outcomes of all adverseevents were analysed [52R]. The most com-mon caspofungin-related adverse eventswere fever (9.3%), chills (5.2%), increased

alanine aminotransferase activity (6.5%),increased aspartate aminotransferase activity(6.0%), and increased alkaline phosphataseactivity (5.2%). Although 27% of thecaspofungin-treated subjects reported seri-ous adverse reactions, only 0.8% wereattributed to caspofungin. Caspofungindose-related toxicity was not observed.

Micafungin [SEDA-32, 510; SEDA-33, 558; SEDA-34, 435]

Observational studies Adverse reactions tomicafungin in children have been studiedin a retrospective analysis of six global trials

(phases I, II, and III) in 296 patients [53C].Two of these studies (91 patients) weredouble-blind and randomized. The patientshad invasive infections and underlying life-

threatening conditions were common.Micafungin was withdrawn because of adverse events in seven (2.4%). Duringthe studies, adverse reactions wererecorded in 93% of the subjects, and 34%had adverse reactions classied as serious.The most common adverse events werevomiting (32%), pyrexia (22%), diarrhea(22%), nausea (21%), and hypokalemia(21%). Of these, 4.7% were at least possi-bly related to micafungin. There was noage-dependency and the data suggested noapparent dose-related effects, nor wereany trends observed with respect to dura-tion of treatment.

Combination studies Two studies of mica-fungin in adults and children with conrmedCandida infections have been reported [54C].The rst compared micafungin (adults100 mg/day; children 2 mg/day) with liposomal

amphotericin B (3 mg/kg/day) in 489 patients.The second compared micafungin (100 or150 mg/day) with caspofungin (50 mg/day witha 70 mg loading dose) in adults. Success rateswith micafungin were generally similar tothose with liposomal amphotericin B andcaspofungin, and there were no differencesbetween patients with and without malignan-cies. The frequencies of serious adverse eventsand withdrawal rates with micafungin weresimilar to those observed with liposomalamphotericin B and caspofungin in patientswith and without malignancies.

Hematology A 70-year-old Japanese manreceiving micafungin developed pure redcell aplasia. [55A]

Thrombotic thrombocytopenic purpurahas been attributed to micafungin [56A].

• A 19-year-old previously healthy man had a

motor vehicle accident and received mica-fungin for Candida albicans infection. After asingle 100 mg dose he became hypotensive,oliguric, and febrile. Thrombotic thrombo-cytopenic purpura was diagnosed and micafun-gin was withdrawn, but 2 days later he died.Autopsy conrmed the presence of dissemi-nated small vessel thrombi.



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